The 2-chlorosulfinylazetidin-4-one compounds produced as intermediates in the improved process of this invention as well as like compounds have been previously described. In U.S. Pat. No. 3,960,851, June 1, 1976, Kukolja et al. describe 3-imido substituted 2-chlorosulfinylazetidin-4-ones, wherein the amino group of the azetidinone is diacylated with a derivative of a dicarboxylic acid, and the conversion of the 3-imido azetidinones to 3-methyl-3-cephems (desacetoxycephalosporins). In U.S. Pat. No. 3,843,682, Oct. 22, 1974, Kukolja et al. also disclose 3-imido-2-chlorosulfinylazetidin-4-ones. Subsequently, Kukolja in U.S. Pat. No. 4,081,440, Mar. 28, 1978, discloses 3-amido-2-chlorosulfinylazetidin-4-one compounds wherein the 3-amino group of the azetidinone is monoacylated. There is also disclosed a process for preparing the 3-amidoazetidinones via treatment of a penicillin sulfoxide ester with an N-chloro halogenating agent.
In U.S. Pat. No. 4,052,387, Oct. 4, 1977, Kukolja discloses a method for the preparation of 3-exomethylenecepham sulfoxides by cyclizing the 3-amido-2-chlorosulfinylazetidin-4-ones with a Friedel-Crafts catalyst or a metathetic cation-forming agent.
Further, Ta-Sen Chou discloses in U.S. Pat. No. 4,075,203, February 21, 1978, an improved process for preparing a 3-exomethylenecepham compound which comprises the use of an alkylene oxide in combination with calcium oxide in the 3-amido-2-chlorosulfinylazetidin-4-one forming step of the overall process.
This invention provides yet a further improvement in the two-step process for preparing 3-exomethylenecepham sulfoxides with penicillin sulfoxide esters via the intermediate 2-chlorosulfinylazetidin-4-ones. The improvement of this invention comprises utilizing in the first step of the process a weakly basic, organic solvent insoluble polymer of polyvinylpyridine cross-linked with e.g. divinylbenzene as the hydrogen chloride acceptor, in the formation of the intermediate 2-chlorosulfinylazetidin-4-one.
The 3-exomethylenecepham sulfoxides are valuable intermediates for cephalosporin antibiotic compounds. For example, they can be converted by ozonolysis of the 3-exomethylene group to 3-hydroxy-3-cephem ester sulfoxides. The latter can be halogenated to provide the corresponding 3-halo-3-cephem esters or the intermediate 3-hydroxy compound can be reacted with a diazoalkane, for example, diazomethane, to provide the corresponding 3-methoxy-3-cephem ester sulfoxide. The sulfoxide form of these compounds can be reduced by known methods, for example, the method described by Murphy et al. in U.S. Pat. No. 3,641,014, Feb. 8, 1972, but especially that described by Hatfield in U.S. Pat. No. 4,044,002, Aug. 23, 1977. Deesterification of the intermediate 3-halo or 3-methoxy esters affords antibiotic compounds. For example, 3-methoxy substituted cephalosporin antibiotics are described by Chauvette in U.S. Pat. No. 3,917,587 and 3,917,588, while Chauvette also describes 3-halo substituted cephalosporin antibiotics in U.S. Pat. Nos. 4,064,343, 3,962,227, and 3,925,372.